1. Field of the Invention
The present invention relates generally to compounds and methods for use in inhibiting cadherin-mediated cell adhesion. The invention is more specifically related to modulating agents capable of inhibiting or disrupting interactions between α-catenin and β-catenin, and to therapeutic methods employing such agents.
2. Description of the Related Art
The ability of cells to recognize and bind to each other is a fundamental property of multicellular organisms. Such recognition and binding allows for the maintenance of tissue integrity and compartments, and prevents the inappropriate movement of cells and macromolecules between tissues. Cell adhesion also contributes to the natural adhesion of synapses in the body to prevent the remodeling of synapses. The molecules that are responsible for cellular recognition and binding are collectively known as cell adhesion molecules (CAMs).
There are many different families of CAMs, including the immunoglobulin, integrin, selectin and cadherin superfamilies, and each cell type expresses a unique combination of these molecules. Cadherins are a rapidly expanding family of calcium-dependent CAMs (see Munro et al., In: Cell Adhesion and Invasion in Cancer Metastasis, P. Brodt, ed., pp. 17–34, RG Landes Co. (Austin Tex., 1996)). Examples of the cadherin superfamily include N (neural)-cadherin, E (epithelial)-cadherin, P (placental)-cadherin, and R (retinal-cadherin). These cadherins (termed the classical cadherins, and abbreviated CADs) are integral membrane glycoproteins that generally promote cell adhesion through homophilic interactions (a CAD on the surface of one cell binds to an identical CAD on the surface of another cell), although CADs also appear to be capable of forming heterotypic complexes with one another under certain circumstances and with lower affinity. CADs have been shown to regulate epithelial, endothelial, neural and cancer cell adhesion, with different CADs expressed on different cell types. CADs also regulate the formation of intercellular junctions, and consequently the establishment of physical and permeability barriers between tissue compartments. If cadherin function is abrogated, such junctions between cells do not form.
The structures of the CADs are generally similar. As illustrated in FIG. 1, CADs are composed of five extracellular domains (EC1-EC5), a single hydrophobic domain (TM) that transverses the plasma membrane (PM), and two cytoplasmic domains (CP1 and CP2). The first extracellular domain (EC1) contains the classical cadherin cell adhesion recognition (CAR) sequence, HAV (His-Ala-Val), along with flanking sequences on either side of the CAR sequence that may play a role in conferring specificity.
Inside the cell, the second cytoplasmic domain (CP2) of the classical cadherins interacts with a cytoplasmic protein known as β-catenin (FIG. 1; designated as β) (see Wheelock et al., Current Topics in Membranes 43:169–185, 1996). This protein exists in a complex with another cytoplasmic protein, known as α-catenin (FIG. 1; designated as α). In the absence of this β-catenin/α-catenin complex, the classical cadherins cannot promote cell adhesion. α-catenin also binds to another cytoplasmic protein, known as α-actinin (FIG. 1; designated as ACT), which in turns interacts directly with actin-based microfilaments (FIG. 1; designated as MF) of the cytoskeleton.
β-Catenin is composed of 13 domains, referred to as arm repeats (FIG. 3; see Wheelock et al., Current Topics in Membranes 43:169–185, 1996). The arm repeat closest to the amino terminus of β-catenin (designated as the first arm repeat) is known to contain the α-catenin binding site. The specific amino acids that are directly involved in mediating the interaction between β-catenin and α-catenin have not previously been identified.
Although necessary for a variety of functions in multicellular organisms, CAM function (especially cadherin function) has been implicated in a range of pathological events, including the survival of cancer cells, the migration of cancer cells (metastasis) and the vascularization of tumors (angiogenesis). In such circumstances, it would be advantageous to modulate cadherin function. In order to develop effective therapeutic agents that modulate cadherin function, it is important to further understand the mechanism of cadherin-mediated cell adhesion.
Accordingly, there is a need in the art for improved methods for modulating cadherin function. The present invention fulfills this need and further provides other related advantages.